Cytokines: abnormalities in major depression and implications for pharmacological treatment

The role of cytokines in depression was first considered when the cytokine interferon resulted in "sickness behaviour", the symptoms of which are similar to those of major depression. The latter is associated with an increase in pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha). These cytokines are potent modulators of corticotropin-releasing hormone (CRH) which produces heightened hypothalamic-pituitary-adrenal axis (HPA) activity characterized by increases in ACTH and cortisol, both of which are reported elevated in major depression. Antidepressant treatment has immunomodulatory effects with increases in the production of IL-10, which is an anti-inflammatory cytokine. This review based on a Medline search from 1980-2003, focuses on the evidence available of cytokine changes in acute stress, chronic stress and major depression. It examines the effects of antidepressant treatment on immune parameters in both animal models and clinical trials. We suggest that future antidepressants may target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.     

Combined treatment with atypical antipsychotics and antidepressants in treatment-resistant depression: preclinical and clinical efficacy

Several clinical reports have documented a beneficial effect of adding atypical antipsychotic drugs to ongoing treatments with antidepressants, particularly selective serotonin reuptake inhibitors, in ameliorating drug-resistant depression. The aim of this paper was to summarize some preclinical evidence describing the mechanism responsible for the therapeutic action of combined treatment with antidepressants and atypical antipsychotics and also some clinical data supporting the efficacy and safety of the augmentation strategy for improving antidepressant-resistant depression using atypical antipsychotics. This analysis is based on five microdialysis studies and nine behavioral studies assessing the impact of combined atypical antipsychotic and antidepressant treatments on extracellular levels of dopamine, serotonin and noradrenaline in the prefrontal cortex of freely moving rats and on antidepressant-induced effects, respectively. In addition, clinical data demonstrating the efficacy and safety of augmentation strategies for treatmentresistant depression using atypical antipsychotics were included. Combined treatment of rats with all studied atypical antipsychotics (olanzapine, risperidone, clozapine and quetiapine) and antidepressants (citalopram, fluoxetine and fluvoxamine) increased the extracellular level of dopamine in the prefrontal cortex compared to a respective drug given alone; in addition, a combination of olanzapine or quetiapine plus fluoxetine or fluvoxamine increased the levels of dopamine and noradrenaline. Moreover, atypical antipsychotics administered in a low dose enhanced the antidepressant-like activity of antidepressants, with (among other mechanisms) the serotonin 5-HT_1A, 5-HT_2A and adrenergic a₂ receptors likely playing an important role in their action. The results support the conclusion that atypical antipsychotics may be effective as adjunctive therapy in treatment-resistant depression; however, their adverse effect profile may be unfavorable in some patients.     

Psychomotor stimulants versus antidepressants in the learned helplessness model of depression

Animal models of depression which use stress to induce abnormal behavior generally cannot discriminate antidepressants from drugs which are central stimulants and predominantly stimulate dopamine (DA) neurons. Thus these models lack pharmacological specificity. The present study shows that the Learned Helplessness (LH) model, applied to Wistar rats, becomes a more valid pharmacological model if registration of the animals' behavior during the interval between each trial of the LH shuttlebox test is added. The DA drugs amphetamine, methylphenidate, nomifensine, apomorphine, quinpirole (specific D2 agonist), SKF 81297 (specific D1 agonist), and the antidepressants imipramine, amitriptyline, and isocarboxazide were tested. The results show that the DA drugs had an acute effect and increased the number of shuttle box crossings in the intervals between the test trials. The antidepressants had no acute effect and did not increase the number of intertrial crossings in the therapeutic dose range. The LH model thus seems to be advantageous when discrimination between drugs with DA psychomotor stimulating properties and drugs with antidepressant properties is needed. © 1993 Wiley-Liss, Inc.     

Cilobamine in the treatment of atypical depression

Sixteen patients meeting our criteria for atypical depression were treated in a 7-week single-blind pilot study with cilobamine mesylate, an investigational antidepressant structurally distinct from tricyclic antidepressants (TCA) and monoamine oxidase inhibitors (MAOI). Nine patients (56 per cent) responded to cilobamine. Cilobamine patients were compared with a group of similar patients receiving placebo for 6 weeks in a separate double-blind study. The response rate to cilobamine was superior to that of placebo. Cilobamine patients also showed significantly greater improvement in Hamilton Depression Scale scores than did placebo patients. Previous studies have demonstrated the efficacy of MAOIs in atypical depression. This study suggests that certain antidepressants which are not MAOIs, and are free of dietary restrictions and the risk of hypertensive crises, may also be effective in atypical depression.     

Comparison of efficacy and tolerability of reboxetine and venlafaxine XR in major depression and major depression with anxiety features: an open label study

OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of reboxetine in the treatment of major depressive disorder (MDD) and MDD with anxiety features to venlafaxine XR. METHOD: Patients with MDD, aging 18 between 65 years, were randomly allocated to two groups receiving either open-label venlafaxine XR capsules (n = 50) or reboxetine tablets (n = 43). Subjects were administered Hamilton Depression Rating Scale (HAM-D) and Hamilton Anxiety Scale (HAM-A) at baseline and 2, 4, 7, 10 weeks after the baseline visit. RESULTS: Response rates to antidepressant treatment were significantly higher in the venlafaxine XR group at 10th week. When patients having anxious depression were analysed separately; response rate for anxiety of reboxetine group was significantly higher at 7th week only. Mean number of side effects were significantly higher in reboxetine group. Only one subject in each group was dropped out due to side effect. CONCLUSION: We may suggest that reboxetine is as effective and tolerable as venlafaxine XR in the treatment of MDD and MDD with anxiety features, and it may be considered a treatment option to venlafaxine XR.     

A study of cardiovascular disease,depression and antidepressants on a computerised general practice database

Previous evidence suggests there is an association between cardiovascular disease and depression. Tricyclic antidepressants (TCAs) are contraindicated in patients with a recent history of cardiovascular disease. 5678 patients between the ages of 50 and 79 years and with a new acute cardiac event were selected from a computerised general practice database and followed up for one year. ‘New episodes’ of diagnosed depression were identified and treatment with antidepressants was investigated. 183 656 patients aged 50–79 years without a cardiac event were used for comparison. A significant association was found between cardiovascular disease and a new diagnosis of depression (adjusted OR=2.23, 95 per cent CI 1.90–2.62). Patients who had suffered a recent cardiac event were less likely to be prescribed a TCA than an SSRI (adjusted OR=0.59, 95 per cent CI 0.41–0.85). However, 35 per cent of patients with a recent cardiac event were initially prescribed a TCA. The findings indicate that general practitioners recognise the dangers of prescribing TCAs to patients with a recent history of cardiovascular disease. However, a substantial minority of cardiac patients were prescribed TCAs where they may not have been the optimal choice. Copyright © 1999 John Wiley & Sons, Ltd.     

非ST段抬高急性冠脉综合征患者GRACE和TIMI危险评分与冠状动脉病变程度的相关性分析

目的：探讨非ST段抬高急性冠脉综合征（ NSTE－ACS）患者全球急性冠状动脉事件注册（ GRACE）评分和心肌梗死溶栓治疗临床试验（ TIMI）危险评分与冠状动脉病变的关系,评价GRACE和TIMI危险评分对NSTEACS患者冠状动脉病变预测的价值。方法收集2010年1月－2013年6月住院的NSTE－ACS患者共108例,以相关临床预测变量对其分别进行GRACE和TIMI危险评分,以及行冠状动脉造影,分析不同危险分层系统中患者冠状动脉病变的特点,及GRACE和TIMI危险评分与冠脉病变之间的关系。结果随着GRACE和TIMI危险评分分值的增加, NSTE－ACS患者冠状动脉狭窄的支数及狭窄的程度呈增加的趋势。结论 GRACE和TIMI危险评分对NSTE－ACS患者冠状动脉病变支数、狭窄严重程度有一定的预测价值。     

The use of antidepressants in bipolar disorder patients with depression

Introduction: The proportion of time that bipolar patients experience depressive symptoms and clinical states, with associated psychosocial impairment and elevated risk of suicide, is significantly greater than the time spent in manic/hypomanic forms of bipolar disorders. Yet, manic states and symptoms have been the focus and interest of most clinical research over the past quarter century. Not a single antidepressant approved for treatment of major depressive disorder, as monotherapy, has received regulatory approval for treatment of bipolar depression as monotherapy, despite their common use in bipolar depression.

Areas covered: We reviewed randomized studies, particularly ones initially intended for registration purposes, and systematic treatment guidelines, in development of this guide to treatment decision and implementation of interventions for depression in bipolar disorders.

Expert opinion: The Expert Opinion section emphasizes strategies, not individual agents. The efficacious performance of mood stabilizers and second-generation antipsychotics as a component of the strategy is strongly supported by published studies. However, this section relies largely on secondary publications and our combined clinical experience, as few randomized, blinded studies have had, as their focus, the comparison of combined regimens for depression. This article summarizes the design features and results of studies dealing with depressive features and intervention strategies for bipolar disorders. The emphasis of the recommendations is on pragmatic treatment decisions that clinicians can make to enhance the probability of both short and long term benefits for patients.     

Neuroendocrine and anthropometric measures in major depression: the effect of antidepressant treatment

It has been suggested that weight change might be associated with certain neuroendocrine abnormalities often observed in patients suffering from a depressive illness. This preliminary study examined whether objective measures of weight change were associated with dexamethasone suppression test (DST) results or plasma levels of thyroid hormones, and whether they correlated with clinical improvement. Specific measures included plasma cortisol following dexamethasone, plasma free thyroxine (T4) and triiodothyronine (T3), as well as anthropometric measures (skinfolds, percentage body fat, body density). The majority of patients (75 per cent) showed some weight gain after treatment. A strong positive correlation was observed between weight gain and plasma tricyclic levels (P<0·005) but only a weak correlation was found between plasma tricyclic levels and therapeutic response (r=0·14). A gender difference was seen in the relationship between weight gain and therapeutic response, with weight gain being associated with less improvement in men and more improvement in women. Therefore, weight gain during treatment may not necessarily indicate clinical improvement for all patients. The only variable that reliably predicted treatment response was free T4. High levels of free T4 prior to treatment were highly correlated with better clinical status as indicated by HAMD scores (r=0·87, P<0·005). Following treatment with imipramine, plasma cortisol levels after dexamethasone administration were reduced in treatment responders but not in nonresponders. Overall, patients that showed the largest decreases in post-dexamethasone cortisol levels from before to after treatment also showed the largest decreases in HAMD total scores (r=0·37) and, especially, somatic anxiety scores (r=0·58, p<0·05). These effects were stronger in women than men. © 1997 John Wiley & Sons, Ltd.     

High dose tertiary amine tricyclic antidepressants in the treatment of severe refractory depression: The central role of plasma concentration estimations

The relationships between dosage, plasma concentration, antidepressant response and toxicity were investigated in 24 highly selected patients with severe, refractory major depression who were prescribed amitriptyline, clompramine or dothiepin at high dosage (150–525 mg/day), usually in combination with lithium or other psychotropics. of serious adverse effects 83 per cent were encountered when tricyclic antidepressant (TCA) plasma concentrations exceeded 400 mcg/1. Therapeutic drug monitoring of high dose TCAs is useful in minimizing the risk of toxicity and in revealing poor compliance, undertreatment and pharmacokinetic interactions which can mitigate against drug efficacy. The value of carbamazepine in the management of refractory depression in the context of unipolar affective disorder is put into question.     

Biochemical profile in patients with anxious depression under the treatment with serotonergic antidepressants with different mechanisms of action

The pharmacodynamics of serotonergic antidepressants that differentially influence serotonin reuptake transporters is poorly investigated. The aim of this study was to compare the biochemical profiles in patients with anxious depression under the treatment with tianeptine, a serotonin reuptake enhancer, and sertraline, a selective serotonin reuptake inhibitor. Platelet monoamine oxidase (MAO) and serum amine oxidase (AO) activities, concentration of middle-mass endotoxic molecules (MMEM) and parameters that characterize the functional properties of serum albumin were investigated in 43 patients with anxious depression (ICD-10: F 32.1 and F 33.1). It was established that, in comparison with healthy controls, patients with anxious depression were characterized by the significant increase in MAO activity (by 95%), MMEM concentration (by 86%), and a significant decrease in AO activity (by 43%) and also in functional albumin activity. The results of the study show that both tianeptine and sertraline are equally effective in the treatment of anxious depression. The present biochemical investigation, however, suggests that the underlying biochemical changes are more complete following tianeptine treatment.     

Moclobemide and sertraline in the treatment of melancholic and nonmelancholic major depression: a comparative study

The objectives of this study were first to compare the responses to moclobemide and sertraline in melancholic and nonmelancholic major depressive patients and secondly to compare the responses of melancholic and nonmelancholic patients in general. Sixty-three patients, with diagnosis of major depression according to the DSM-III-R criteria were included in the study. In this single blind, comparative, randomized study, 29 patients were treated with moclobemide and 34 patients were treated with sertraline for 13 weeks. A 50 per cent decrease of the HDRS (Hamilton Depression Rating Scale) is defined as response.In intent-to-treat analysis the response rates were 69 per cent in the melancholic patients and 59·3 per cent in the nonmelancholic group. The difference is statistically insignificant. According to the intent-to-treat analysis in the nonmelancholic group the response rate of the moclobemide-treated patients was 73·3 per cent, and 41·7 per cent in the sertraline-treated patients. In the melancholic group the response rate was 82·4 per cent in the sertraline group and 50 per cent in the moclobemide group. Moclobemide was more effective in the nonmelancholic group whilst sertraline was more effective in melancholic group; but the differences were not statistically significant. Due to the small size our findings are tentative and need confirmation using more patients. © 1998 John Wiley & Sons, Ltd.     

Antidepressant agents for the treatment of chronic pain and depression

Depression and painful somatic symptoms commonly occur together. Depression and chronic pain can have devastating effects on a patient's health, productivity, and overall quality of life. When moderate-to-severe pain exists, it can impair patient function while making treatment more difficult or resistant, with increased severity in depressive symptoms and worse outcomes. A variety of chronic pain syndromes exist, including diabetic neuropathy. A high prevalence of patients with chronic pain display depressive symptoms. Treatment for these conditions relies on pharmacologic therapy coupled with diligent, periodic assessments of changes in symptom severity. The link between pain and depression lies in the central and peripheral nervous systems. The brain stem serves as an important connection between the higher brain centers and the spinal cord. In the brain stem, the neurotransmitters serotonin and norepinephrine modulate pain transmission through ascending and descending neural pathways. Both serotonin and norepinephrine are also key neurotransmitters involved with the pathophysiology of depression. Tricyclic antidepressants are effective treatments for pain and depression; selective serotonin reuptake inhibitors provide less benefit. Duloxetine and venlafaxine, which are serotonin and norepinephrine reuptake inhibitors, were shown in clinical trials to alleviate pain and depressive symptoms. Diabetic neuropathy and other chronic pain syndromes were also shown to benefit from duloxetine and venlafaxine. Antidepressants remain fundamental therapeutic agents for depression and anxiety disorders. Their extended use into chronic pain, depression with physical pain, physical pain with or without depression, and other potential medical conditions should be recognized.     

奥沙西泮联合阿米替林治疗抑郁症的临床研究

目的 探讨奥沙西泮联合阿米替林治疗抑郁症的临床疗效。方法 选取2020年12月-2021年12月芜湖市第四人民医院精神科诊疗的100例伴躯体症状抑郁症患者,按照随机数字表法分为对照组和治疗组,每组各50例。对照组患者口服盐酸阿米替林片, 25 mg/次, 3次/d。治疗组在对照组的基础上口服奥沙西泮片, 30 mg/次, 3次/d。两组患者持续治疗8周。观察两组的临床疗效和症状改善时间。比较两组治疗前后汉密尔顿抑郁量表(HAMD)评分、症状自评量表(SCL-90)评分及血清白细胞介素6(IL-6)、白细胞介素2(IL-2)、肿瘤坏死因子(TNF-α)、白细胞介素1β(IL-1β)水平的变化情况。结果 治疗后,治疗组总有效率是98.0%,显著高于对照组的80.0%(P<0.05)。经治疗,治疗组出现入睡困难、食欲下降、疲乏无力、情绪烦躁等症状改善时间均显著短于对照组(P<0.05)。治疗后,两组HAMD评分、SCL-90评分均较治疗前显著降低(P<0.05);治疗后,治疗组HAMD评分、SCL-90评分均低于对照组(P<0.05)。治疗后,两组血清IL-6、IL-2、TNF-α、IL-1β水平均较治疗前显著降低(P<0.05);治疗组血清学指标水平低于对照组(P<0.05)。结论 奥沙西泮联合阿米替林治疗伴躯体症状抑郁症效果确切,可明显改善症状,降低炎性细胞因子,值得临床推广。     

An update on the treatment of bipolar depression

Background: Although depression accounts for a large part of the burden associated with bipolar disorder, its drug treatment has been under-studied. Objective: To provide the best available evidence supporting the pharmacotherapy of bipolar depression. Methods: A systematic review was conducted, focusing on randomized, controlled trials (RCTs) and meta-analyses. Results/conclusions: Despite FDA approval of both the olanzapine–fluoxetine combination and quetiapine for the treatment of acute bipolar depression, independent RCTs (i.e., not trials conducted ‘under the umbrella’ of a drug company) have not found any drug to have antidepressant effects similar to those seen in unipolar depression. A practice-based suggestion, valuable for both short- and long-term treatment, might be to have a background of mood stabilizers and to add drugs, following one of several treatment options, trusting to find a drug with a degree of effectiveness by trial and error. The list of drugs that could be used would include all the current antidepressants, the olanzapine–fluoxetine combination and probably quetiapine too. Special features and situations might also influence treatment options.     

Effect of treatment with some atypical antidepressants on 3H-DHA binding in rat brain

The mechanism of therapeutic action of antidepressant drugs has been related to their effects on metabolism and release and reuptake of catecholamines and serotonin. Some atypical antidepressants, however, do not have such pharmacological effects. Recently it has been reported that most of the antidepressant drugs cause down regulation of beta adrenergic receptors in rat brain after chronic treatment. In order to examine if this is a common and specific pharmacologic property of all antidepressant drugs, we have studied the effects of treatment with some atypical antidepressant drugs on beta adrenergic receptor binding in rat cortex using ³H-dihydroalprenolol (DHA) as the radiolabeled ligand. Our results indicate that chronic treatment with almost all antidepressants studied causes down regulation of beta adrenergic receptors. However, such effects are not observed after treatment with neuroleptics such as haloperidol or chlorpromazine or psychomotor stimulants such as cocaine. This approach thus provides a useful method of screening potential antidepressant drugs.     

Blatchford评分对预测消化性溃疡出血患者选择内镜下治疗的初步研究

目的比较Blatchford和内镜前Rockall评分对消化性溃疡出血患者是否需要胃镜下治疗的预测价值。方法选取2009年1月至2012年7月在我院住院治疗的382例确诊为消化性溃疡出血患者,入院后给予药物治疗及内镜下治疗,并统计Blatchford和内镜前Rockall评分。结果 382例消化道溃疡出血患者中,120例（31.4%）需要进行内镜下治疗。按照Blatchford评分系统,中高危组需要进行内镜下治疗率明显高于低危组,差异具有统计学意义。需要内镜下治疗患者的Blatchford评分（9.6±4.2）要显著高于不需要治疗的患者（6.5±3.5）（P〈0.05）。而按照内镜前Rockall评分系统,无法通过评分来明确区分是否需要进行内镜下治疗。结论 Blatchford评分能更准确的判断患者是否需要内镜下治疗,特别是评分为0是不需要进行内镜下治疗。而Rockall评分不能用来对低风险进行判断。